The long-term objectives of this research are to improve natural product drug discovery strategies and to use these improved strategies to discover new compounds that have the potential to be useful in treating Alzheimer's disease or as a tool for studying the biochemistry and physiology of Alzheimer's disease. The need for this research is substantial given the lack of any FDA approved drug therapies that have a significant effect on the progression of the disease. In that vein, the specific goals of this project are: 1. To develop an innovative BACE1 screening protocol that, for the first time, rapidly links a single compound within a mixture to the observed biological activity. This protocol combines a chemiluminescent assay, performed in 96-well plates, in series with a LC-MS homogeneous affinity assay. 2. To isolate and structurally characterize new substances from cyanobacteria and sponges testing positive in either screening assay, in order to test the hypothesis that natural products derived from these sources are a rational source of Alzheimer's drug leads. 3. To evaluate these compounds as potential BACE1 inhibitors. Compounds will be initially examined for potency, cellular activity, neuroprotective effect, BBB permeability, and PgP interactions with further evaluations conducted as warranted. PUBLIC HEALTH RELEVANCE: The long-term objectives of this research are to improve natural product drug discovery strategies and to use these improved strategies to discover new compounds that have the potential to be useful in treating Alzheimer's disease or as a tool for studying the biochemistry and physiology of Alzheimer's disease. The need for this research is substantial given the lack of any FDA approved drug therapies that significantly affect the progression of the disease.